Methods and materials for embolization

Abstract

The present disclosure relates to methods and materials for embolization of one or more blood vessels (e.g., one or more arteries). For example, hydrogel compositions for embolization of one or more blood vessels (e.g., one or more arteries) in a mammal (e.g., a human) are provided.

Description

[Technical field]

[0001] The present disclosure relates to methods and materials for embolization of one or more blood vessels (e.g., one or more arteries). For example, the present disclosure provides hydrogel compositions for embolization of one or more blood vessels (e.g., one or more arteries) in a mammal (e.g., a human). [Background technology]

[0002] Bleeding during anticoagulation therapy (ACA) is a serious medical emergency with high morbidity and mortality. In the United States alone, there are more than 2.6 million people with ACA and atrial fibrillation (Non-Patent Document 1). More than 30 million prescriptions for Coumadin are written annually, and prescriptions for newer oral anticoagulants are being written on an increasing basis. The incidence of bleeding with Coumadin alone is estimated at 15-20 percent per year (Non-Patent Document 2 and Non-Patent Document 3). The risk of bleeding is even higher in patients with mechanical valves and cardiac assist devices (CAD) (Non-Patent Document 4, Non-Patent Document 5, and Non-Patent Document 6).

[0003] Liquid emboli, introduced 15 years ago, are specially formulated substances designed to self-clot upon deployment in situ. Once injected, liquid emboli transform into solids based on physicochemical mechanisms such as polymerization, precipitation, and cross-linking by ionic, covalent, or thermal processes. However, liquid emboli carry risks such as catheter entrapment (Non-Patent Document 7), recanalization rates of up to 36% (Non-Patent Document 8), and leakage during injection that can cause non-target embolization, angiotoxicity, and / or necrosis. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Lloyd-Jones et al., Circulation, 121:948 (2010) [Non-Patent Document 2] Wysowski et al., Arch. Intern. Med., 167:1414 (2007) [Non-Patent Document 3] Zareh et al., West. J. Emerg. Med., 12:386 (2011) [Non-Patent Document 4] Eckman et al., Circulation, 125:3038 (2012) [Non-Patent Document 5] Kirley et al., Circ. Cardiovasc. Qual. Outcomes, 5:615 (2012) [Non-Patent Document 6] Smith et al., J. Thorac. Dis., 7:2112 (2015) [Non-Patent Document 7] Qureshi et al., J. Vasc. Interv. Neurol., 8:37 (2015) [Non-Patent Document 8] Cekirge et al., Neuroradiology, 48:113 (2006) Summary of the Invention

[0005] The present disclosure provides methods and materials for embolization of one or more blood vessels (e.g., one or more arteries). For example, the present disclosure provides hydrogel compositions for embolization (e.g., reversible embolization) of one or more blood vessels (e.g., one or more arteries) in a mammal (e.g., a human).

[0006] As demonstrated herein, radiopaque hydrogel compositions (e.g., gel embolic materials (GEMs)) comprising 18% (w / v) gelatin type A, 9% (w / v) silicate nanoplatelets, and either 10% (w / w) iohexol or 20% (w / w) tantalum particles can be rapidly delivered to diseased vessels (e.g., veins or arteries) using clinical catheters to achieve embolization of primary arteries, such as the renal and iliac arteries. Also, as demonstrated herein, embolization using radiopaque GEMs comprising 18% (w / v) gelatin type A, 9% (w / v) silicate nanoplatelets, and either 10% (w / w) iohexol or 20% (w / w) tantalum particles can be visualized in vivo using multiple imaging platforms.

[0007] The ability to deliver a hydrogel composition comprising gelatin, nanosilicate, and one or more radiopaque contrast agents to perform embolization in a mammalian (e.g., human) blood vessel provides a unique and unrealized opportunity to safely and rapidly achieve hemostasis in one or more blood vessels in a mammal that can be visualized and monitored (e.g., during and / or after delivery). For example, a hydrogel composition comprising gelatin, nanosilicate, and one or more radiopaque contrast agents can be used to treat bleeding, such as hemorrhage (e.g., bleeding in an internal organ). For example, a clinical catheter is used to deliver the hydrogel composition provided herein for efficient, effective, safe, and / or cost-effective embolization.

[0008] In general, one aspect of the disclosure features a hydrogel composition that includes (a) gelatin, (b) a nanosilicate, and (c) a radiopaque contrast agent. The hydrogel composition can include about 0.1% (w / v) to about 20% (w / v) gelatin. The hydrogel composition can include 18% (w / v) gelatin. The gelatin can be type A gelatin. The hydrogel composition can include about 3% (w / v) to about 9% (w / v) nanosilicate. The hydrogel composition can include about 9% (w / v) nanosilicate. The nanosilicate can be silicate nanoplatelets. The hydrogel composition can include about 2% (w / w) to about 30% (w / w) radiopaque contrast agent. The hydrogel composition may include about 10% (w / w) radiopaque contrast agent, which may include iohexol. The hydrogel composition may include about 20% (w / w) radiopaque contrast agent, which may include tantalum particles. The viscosity of the hydrogel composition may be about 10. -1 The hydrogel composition may have a displacement pressure of about 15 KPa to about 45 KPa.

[0009] In another aspect, the disclosure features a method for embolization of a blood vessel in a mammal. The method can include, or can consist essentially of, delivering a hydrogel composition including gelatin, nanosilicate, and a radiopaque contrast agent to a blood vessel in the mammal. The mammal can be a human. The delivery can include catheter-guided delivery. The delivery can include a delivery rate of about 1 mL / min to about 2 mL / min. The delivery can include about 2 mL to about 5 mL of the hydrogel composition.

[0010] In another aspect, the disclosure features a method for reducing blood flow in a blood vessel in a mammal. The method can include, or consist essentially of, delivering a hydrogel composition to a blood vessel in the mammal, the hydrogel composition including gelatin, nanosilicate, and a radiopaque contrast agent. The mammal can be a human. The delivery can include catheter-guided delivery. The delivery can include a delivery rate of about 1 mL / min to about 2 mL / min. The delivery can include about 2 mL to about 5 mL of the hydrogel composition.

[0011] In another aspect, the disclosure features a method for inducing clotting in a blood vessel in a mammal. The method can include, or can consist essentially of, delivering a hydrogel composition to a blood vessel in a mammal, the hydrogel composition including gelatin, nanosilicate, and a radiopaque contrast agent. Clotting can be induced in less than about 20 minutes after delivery. Clotting can occur in blood vessels of about 0.5 cubic centimeters (cm 3 ) ~ approx. 5cm 3 The method may include forming a blot having a volume of about 1 mL / min to about 5 mL of the hydrogel composition. The mammal may be a human. The delivery may include catheter-guided delivery. The delivery may include a delivery rate of about 1 mL / min to about 2 mL / min. The delivery may include about 2 mL to about 5 mL of the hydrogel composition.

[0012] In another aspect, the disclosure features a method for treating a mammal having a bleeding disorder. The method can include, or can consist essentially of, delivering a hydrogel composition including gelatin, nanosilicate, and a radiopaque contrast agent to a blood vessel in the mammal. The bleeding disorder can be atraumatic hemorrhage, traumatic hemorrhage, saccular aneurysm, vascular malformation, endoleak, gastroesophageal varices, or arteriovenous fistula. The mammal can be a human. The delivery can include catheter-guided delivery. The delivery can include a delivery rate of about 1 mL / min to about 2 mL / min. The delivery can include about 2 mL to about 5 mL of the hydrogel composition.

[0013] In another aspect, the disclosure features a method for treating a mammal having a tumor. The method can include, or can consist essentially of, delivering a hydrogel composition including gelatin, nanosilicate, and a radiopaque contrast agent to a blood vessel in the mammal that feeds the tumor in the mammal. The tumor can be a benign tumor. The tumor can be a malignant tumor. The tumor can be a liver tumor, a uterine fibroid tumor, a prostate tumor, a kidney tumor, or a brain tumor. The mammal can be a human. The delivery can include catheter-guided delivery. The delivery can include a delivery rate of about 1 mL / min to about 2 mL / min. The delivery can include about 2 mL to about 5 mL of the hydrogel composition.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although the present invention can be carried out using methods and materials similar or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0015] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will become apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0016] [Figure 1]A rat model of femoral artery embolization using GEM. Images of the rat femoral artery (FA; arrow) before (Figure 1A) and after (Figure 1B, arrow) GEM infusion. Laser speckle contrast microperfusion imaging (LSCI) of the exposed FA before (Figure 1C, arrow) and after (Figure 1D, arrow) GEM infusion shows no blood flow. In Figure 1E, digital subtraction angiography from a catheter in the distal aorta shows GEM occlusion of the right femoral artery (arrows indicate collateral arteries bypassing the GEM occlusion). Figure 1F is a panel of representative hindlimb microperfusion images using LSCI at baseline, day 3, day 7, and day 21 after GEM embolization of the FA (arrows), with the contralateral limb being an untreated control. FIG. 1G is a quantitative analysis of LSCI hindlimb perfusion after GEM embolization at baseline, day 0, day 1, day 3, day 7, day 14, and day 21 (*p<0.0001 compared to baseline; n=6). FIG. 1H is a reconstructed maximum intensity projection (MIP) image of FA showing GEM with contrast agent in the lumen of the embolized artery (arrow) at days 0, 3, 7, and 21, which show time-dependent structural changes of GEM in the artery suggesting ongoing remodeling of the material (* at day 0 indicates GEM in the external circumflex artery). FIG. 1I is an H&E stained cross-section of FA embolized with GEM at days 0 and 21, where the arrow at day 0 indicates complete occlusion of the arterial lumen by GEM. The arrow at day 21 indicates remodeling with almost complete replacement of GEM by granulation tissue in the lumen of the FA. [Diagram 2]Assessment of GEM visibility by multiple imaging modalities. Figure 2A shows CT axial images of eight syringes loaded with 0–30% Ta-GEMs inside a phantom simulating a human breast. 20% Ta-GEMs (dashed outline) show similar Hounsfield units (Figure 2B) when compared to 30% Ta-GEMs or 50% iohexol GEMs (n=4). Figure 2C shows fluoroscopic images of syringes loaded with GEMs containing 10% iohexol, 20% Ta nanoparticles (Nano-Ta), or 20% Ta microparticles (Micro-Ta), and quantification of the mean pixel intensity on the fluoroscopic images showed that 20% Micro-Ta yielded the highest intensity (Figure 2D; n=4). Figure 2E and Figure 2F show ultrasonographic and fluoroscopic images, respectively, during percutaneous hepatic vein embolization in pigs using 20% ​​Ta-GEMs (white arrows). Figure 2G is a graphical summary of shear wave elastography of GEMs containing 0-30% Ta microparticles (n=3). Figure 2H is a cross-sectional view of standard T1 and T2 MR imaging of a syringe loaded with 20% Ta-GEM, showing attenuation for the T1 sequence and bright signal for the T2 sequence. In Figure 2I, the T1 and T2 signals of muscle and liver were calculated for an MRI phantom. Figure 2J and Figure 2K are graphical representations of the T1 and T2 signals of 20% Ta-GEM against the calculated signal (Figure 2I). These show that the signal intensity is greater than muscle or liver, suggesting that 20% Ta-GEMs are visible in MRI. Figure 2L is a scanning electron micrograph of a 20% Ta-GEM (white arrow, tantalum microparticles). Figure 2M is a micro-CT image of a syringe loaded with 20% Ta-GEM showing a homogenous distribution of Ta in the GEM. Data are means ± SD (**P<0.01, ***P<0.001, ****P<0.0001). [Diagram 3]Physical and mechanical characterization of Ta-GEM. Figure 3A is a schematic of the injection force test. The table shows the catheters and parameters used during the test (ID: inner diameter of the catheter). Figure 3B is a representative injection force curve of GEM and Ta-GEM in a 1 mL syringe injected at 1 mL / min through a 110 cm, 2.8 F microcatheter. Figure 3C is a summary of the break loose force and injection force of GEM and Ta-GEM in a 2.8 F microcatheter system (n=5). Figure 3D is a representative injection force curve of GEM and Ta-GEM, respectively, loaded into a 3 mL syringe and injected at 2 mL / min through a 100 cm, 5 F catheter. Figure 3E is a summary of the break loose force and injection force of GEM and Ta-GEM in a 5 F catheter system (n=5). FIG. 3F: Injection force profile of interrupted delivery (10 sec delivery followed by 5 sec residence time) of Ta-GEM through a 5F catheter at 2 mL / min. In FIG. 3G: Flow curves comparing GEM and Ta-GEM at 37° C. show shear thinning properties. FIG. 3H: Amplitude sweep of GEM and Ta-GEM at 37° C. FIG. 3I: Summary of storage modulus kinetics of GEM and Ta-GEM at 25° C. and 37° C. (n=3). Data are mean±SD for FIG. 3C, FIG. 3E, and FIG. 3I. FIG. 3J: Resistance pressure curves in an in vitro embolization study. FIG. 3K: Summary of graphs showing that peak pressure is greatest generated by Ta-GEM+coil compared to coil alone (**p<0.01, ***p<=0.001, ****p<0.0001, data represent mean±SD, n=3). Figure 3L shows photographs of the coil fiber inside the vascular model after catheter delivery of GEM (shown in green) before and after injection. [Figure 4]Evaluation of Ta-GEM embolization in anticoagulated porcine iliac arteries. Figures 4A-4C are schematics of transcatheter arterial embolization with Ta-GEM. Figure 4D is a digital subtraction angiogram (DSA) showing failure of the coil to achieve occlusion (black arrow; contrast agent flows through the coil mass in the artery), while the white arrow in the contralateral iliac artery shows complete occlusion of the artery with Ta-GEM. In Figure 4E, contrast agent injection into the iliac artery shows contrast agent flowing through the coil mass (black arrow) and beyond (white arrow). After delivery of GEM to the coil mass in Figure 4E, the DSA image in Figure 4F shows complete occlusion without breakthrough of blood flow (arrows). With respect to Figure 4G, the coronal micro-CT image in Figure 4F shows the GEM (arrowhead) uniformly casting the internal iliac artery without artifacts, in contrast, the coil mass (arrow) generated large streak artifacts that limited evaluation of the artery and adjacent branches. In Figure 4H-J, sequential DSA images of a normal porcine pelvic artery in Figure 4H, a left internal iliac artery embolized with Ta-GEM in Figure 4I (arrow), and a DSA after complete retrieval of the Ta-GEM in Figure 4J show restoration of blood flow in the artery. Retrieval of the Ta-GEM was performed 3 hours after embolization of the artery. [Diagram 5]Computed tomography and histology evaluation of porcine internal iliac artery occlusion. Figure 5A shows a panel of micro-CT images and corresponding cross-sections of the internal iliac artery on histology at 0, 1, 2, or 4 weeks post-embolization stained with H&E, VG-elastin, Masson's trichrome, and myeloperoxidase (MPO), respectively. At day 0, there is homogenous occlusion of the artery by Ta-GEM (arrows). This is followed by a concentric fibroinflammator reaction and biodegradation of the GEM. Figure 5B shows a 3D coronal rendering of reconstructed high-resolution micro-CT scans of excised porcine internal iliac arteries after segmentation of Ta-GEM inside each vessel at 0, 1, 2, or 4 weeks post-embolization (arrows point to GEM, black is inside the artery; connective tissue is shown in gray). Over time, there is progressive biodegradation of the Ta-GEM and increased fibrosis (gray). Figure 5C shows a reconstructed linear depiction from the aorta to the iliac arteries, showing Ta-GEMs medial to the left internal iliac artery (arrow) and the patent right internal iliac artery (arrowhead). Figure 5D shows a graph quantifying Ta-GEMs over time from the micro-CT segmented dataset in Figure 5B, revealing a gradual decrease in GEMs within the arteries. Data are mean ± SEM, n=4, *p<0.0001, **p=0.007, using ANOVA and Tukey's post-hoc analysis. [Figure 6]Porcine renal artery embolization with Ta-GEM and comparison with gelfoam. Fluoroscopic images before (Figure 6A) and after (Figure 6B) renal artery embolization with Ta-GEM, showing complete loss of renal artery flow to the kidney after injection of 2-3 mL of Ta-GEM (arrows). In Figure 6C, a maximum intensity projection image shows the left main renal artery and segmental branches occluded with Ta-GEM (arrows). Axial CT (Figure 6D) and 3D reconstructed image (Figure 6E) show a grossly atrophied kidney with Ta-GEM in the renal artery. Figures 6F-I are representative coronal CT images of kidneys embolized with Ta-GEM at 0, 1, 2, or 4 weeks, respectively. No Ta-GEM is present in the cortex of the kidney. Figure 6J is a photograph showing the gross appearance of an embolized kidney at 4 weeks with compensatory hypertrophy of the contralateral kidney. Figure 6K: Summary of total kidney volume measurements after renal artery embolization (***p<0.001, ****p<0.0001 using one-way ANOVA, n=4 per group). Over time, kidney atrophy progresses. DSA images before (Figure 6L) and after (Figure 6M) embolization of the renal artery with Gelfoam (black arrows). In Figure 6N, 2 weeks after embolization, axial CT images show enhanced blood flow in the embolized kidney and artery despite successful renal artery embolization (dashed outline). Data reported as mean ± SEM. [Figure 7]Time-dependent characterization of morphological changes of GEMs in rat femoral arteries using micro-CT and histology. In A-D, micro-CT analysis of surface-to-volume ratio, surface convexity index, fractal dimension, and structural model index, respectively, show structural changes of GEMs inside rat FAs. Representative FA tissue sections stained with Verhoeff-Van Gieson (E), Masson's trichrome stain (F), myeloperoxidase (MPO) and CD68 (H). I and J, Graphs of time-dependent changes in medial thickness and luminal area at different time points after embolization. K, Graphical summary of the average number of MPO-expressing cells per high-power field for each time point showing significant granulocytic infiltration at day 3 and a decrease by days 7 and 21. L, Graph showing summary of the average number of CD68-expressing cells per high-power field demonstrating significant recruitment of macrophages at day 21 after GEM embolization. Data are means ± SEM (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001; n=6). Scale, 200 μm. [Figure 8] Embolization of the rat femoral artery under anticoagulation. Laser speckle contrast imaging (LSCI) of the femoral artery and vein in heparinized rats shows a patent femoral artery at baseline (A; arrow) and complete occlusion after embolization with GEM (B; white arrow). C, Graph showing significant increase in activated clotting time (ACT) after heparin injection compared to baseline, confirming anticoagulation. D, Coronary micro-CT images of isolated femoral arteries using Ta-GEM from anticoagulated and control rats 3 days after embolization. In E, quantitative analysis of hindlimb perfusion using LSCI suggests no difference between anticoagulated and normal rats 1 and 3 days after embolization, with no evidence of fragmentation or migration (n=6). In F and G, histological micrographs of rat femoral artery cross sections obtained from anticoagulated or untreated rats 3 days after embolization, respectively, show that GEM persistently cast both vascular lumens. Data are means ± SEM (***P<0.001, ****P<0.0001; n=6). Scale, 650 μm. [Figure 9]Evaluation of the effect of tantalum microparticles on blood thrombogenicity and GEM sterility. A, Time to clot formation when blood alone, GEM, Ta-GEM, and clinically used embolic coils were mixed with blood. GEM, Ta-GEM, and coil samples showed evidence of clot formation as early as 4 minutes. In B, the average mass of clot formed over time shows enhanced thrombogenicity with Ta-GEM compared to blood alone or GEM alone. C, Graphical summary of sterility testing of GEM and GEM-Ta after inoculation of LB broth and incubation at 37°C for 24 hours, compared to LB broth alone and LB broth inoculated with E. coli. Optical density was measured at 600 nm for each aliquot. Results are mean ± SEM (**P<0.01, ****P<0.0001; n=4). [Figure 10] Catheter-guided delivery and retrieval of Ta-GEM from porcine arteries. A-C show sequential digital subtraction angiography (DSA) images upon Ta-GEM injection into the iliac artery (see Movie S1 for real-time video). These images demonstrate immediate occlusion upon exiting the catheter without distal fragmentation. D shows the iliac artery containing Ta-GEM at necropsy (arrow). E-H are representative images of the internal iliac artery that was first embolized with Ta-GEM (E; white arrow) and then retrieved using a Penumbra aspiration catheter (yellow arrows (F,G)). H shows restoration of flow after retrieval of GEM. [Figure 11]Assessment of arterial occlusion and organ integrity in pigs by computed tomography angiography 4 weeks after embolization. In A, a 3D image reconstructed from contrast-enhanced CT angiogram shows the absence of the right internal iliac artery (red arrow), which is not opacified as it is occluded with Ta-GEM. An axial image of the yellow dotted circle in (A) is displayed in (B). In B, the red circle indicates no flow in the embolized artery, with segmental hypodensity in the gluteal muscle (white arrow) showing evidence of ischemia. The contralateral artery (small yellow circle) is widely patent with no evidence of hypodensity or ischemia in the respective gluteal muscle (blue arrowhead). An axial image of the blue dotted circle in (A) is displayed in (C). In C, an axial image of the distal hind limb shows normal outflow vessels to the foot (arrows), suggesting no evidence of non-target embolization. Panels of axial CT images of the brain (D), heart (E), lungs (F), liver (G), spleen (H), kidneys (I), pelvis (J, K), and hind limbs (L) show normal radiographic findings. [Figure 12] Quantitative analysis and histology of inflammatory cell infiltration after internal iliac artery embolization. A, Summary graph of the average number of MPO-expressing cells in the lumen of porcine internal iliac arteries embolized with Ta-GEM, showing significant infiltration of MPO-expressing cells at 2 weeks post-embolization (**p=0.004, using ANOVA with Kruskal-Wallis post-hoc test). In B, graph of MPO-expressing cells infiltrating into the arterial wall compartment shows a significant increase at 2 weeks post-embolization. **p=0.007, using ANOVA with Tukey's post-hoc test. Data are mean ± SEM, n=4 for each data point. In C, histology, trichrome staining shows an intact medial layer at day 0 post-embolization. However, in D, at day 14, there is destruction and fibrosis of the medial layer. In E, elastin staining of the medial layer shows destruction of the intimal and medial layers. Scale bar 50 micrometers. [Figure 13]Evaluation of intravascular distribution of Ta-GEM after renal artery embolization in pigs using a Fogarty catheter. In A, a 4 French Fogarty catheter in the central main renal artery was inflated and Ta-GEM was continuously infused until the balloon began to displace proximally. Following coronal sectioning of the kidney at necropsy, near-infrared imaging of this kidney embolized with Ta-GEM containing indocyanine green showed distribution of GEM in the main renal artery and segmental arteries excluding the cortex. In B, a transverse section across the inferior pole shows an arteriole embolized with Ta-GEM (arrow). In C, H&E of a slide showing the cortex demonstrates normal glomeruli with no Ta-GEM present in the cortex. D, H&E image showing an interlobar arteriole embolized with Ta-GEM. (Scale; 500 μm). In E, the whole kidney from (A) was imaged ex vivo in a micro-CT scanner. These images show intravascular embolic material reaching the proximal arcuate arteriole. In F, a graphical summary of arterial diameters measured in the four kidneys reveals that the mean vessel diameter of the smallest embolized arteries was in the range of 320 μm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In describing the embodiments, reference may be made to the accompanying drawings, which form a part of this specification and which show by way of illustration specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention. Unless otherwise defined, all technical terms, notations, and other scientific or technical terms used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention belongs. In some cases, terms having commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference to what is generally understood in the art. Many of the aspects of the techniques and procedures described or referenced herein are well understood and commonly used by those skilled in the art. The following text describes various embodiments of the present invention.

[0018] The present disclosure provides methods and materials for embolization of one or more blood vessels (e.g., one or more arteries) in a mammal (e.g., a human). For example, the present disclosure provides hydrogel compositions that can be delivered to one or more blood vessels (e.g., one or more arteries) in a mammal (e.g., a human) for embolization of the blood vessel. In some cases, one or more hydrogel compositions provided herein can be delivered to one or more blood vessels in a mammal (e.g., a human) to induce the formation of a thrombus (e.g., an artificial embolism) in the blood vessel. In some cases, one or more hydrogel compositions provided herein can be delivered to one or more blood vessels in a mammal (e.g., a human) to form an embolism (e.g., an artificial embolism) in the blood vessel.

[0019] The hydrogel compositions provided herein may include gelatin, one or more nanosilicates, and one or more radiopaque contrast agents. In some cases, the hydrogel compositions provided herein may be sterile. In some cases, the hydrogel compositions provided herein may be antibacterial. In some cases, the hydrogel compositions provided herein may be bioactive. For example, the hydrogel compositions provided herein may include one or more therapeutic agents.

[0020] The hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may include any type of gelatin. In some cases, the hydrogel compositions may include a single type of gelatin. In some cases, the hydrogel compositions may include two or more (e.g., two, three, four, or more) types of gelatin. In some cases, the gelatin may be synthetic gelatin. In some cases, the gelatin may be extracted from animal tissues (e.g., skin, bone, and connective tissue). Examples of types of gelatin that may be included in the hydrogel compositions provided herein include, but are not limited to, type A gelatin, type B gelatin, gelatin extracted from cows, gelatin extracted from pigs, and gelatin extracted from fish.

[0021] Hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can include any amount of gelatin. For example, hydrogel compositions provided herein can include from about 0.1% (w / v) to about 20% (w / v) gelatin (e.g., from about 0.5% (w / v) to about 20% (w / v) gelatin, from about 1% (w / v) to about 20% (w / v) gelatin, from about 5% (w / v) to about 20% (w / v) gelatin, from about 10% (w / v) to about 20% (w / v) gelatin, from about 2 ... 0% (w / v) gelatin, about 12% (w / v) to about 20% (w / v) gelatin, about 15% (w / v) to about 20% (w / v) gelatin, about 17% (w / v) to about 20% (w / v) gelatin, about 0.1% (w / v) to about 18% (w / v) gelatin, about 0.1% (w / v) to about 15% (w / v) gelatin, About 0.1% (w / v) to about 12% (w / v) gelatin, about 0.1% (w / v) to about 10% (w / v) gelatin, about 0.1% (w / v) to about 8% (w / v) gelatin, about 0.1% (w / v) to about 5% (w / v) gelatin, about 0.5% (w / v) to about 18% (w / v) gelatin, about 1% (w / v) to about 15% (w / v) gelatin, about 0.1% (w / v) to about 10 ... % (w / v) gelatin, about 5% (w / v) to about 12% (w / v) gelatin, about 8% (w / v) to about 10% (w / v) gelatin, about 1% (w / v) to about 5% (w / v) gelatin, about 5% (w / v) to about 10% (w / v) gelatin, or about 10% (w / v) to about 15% (w / v) gelatin. In some cases, the hydrogel compositions provided herein may contain about 18% (w / v) gelatin (e.g., type A gelatin). In some embodiments, the hydrogels of the present disclosure comprise from about 0.2% to about 1.2% (w / w) gelatin (including about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, and about 1.2% and all values ​​and ranges therebetween). In some embodiments, the hydrogels of the present disclosure comprise from about 0.6% to about 1.0% (w / w) gelatin. In some embodiments, the hydrogels of the present disclosure comprise from about 0.4% to about 0.8% (w / w) gelatin.In some embodiments, the hydrogels of the present disclosure comprise about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, or about 1.2% (w / w) gelatin. In some embodiments, the hydrogels of the present disclosure comprise about 0.6% (w / w) gelatin. In some embodiments, the hydrogels of the present disclosure comprise about 0.8% (w / w) gelatin.

[0022] The hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may include any type of nanosilicates. In some cases, the hydrogel compositions may include a single type of nanosilicates. In some cases, the hydrogel compositions may include two or more (e.g., two, three, four, or more) types of nanosilicates. Examples of nanosilicates that may be included in the hydrogel compositions provided herein include, but are not limited to, lithium magnesium sodium silicates, such as Laponite®-based silicate nanoplatelets (e.g., Laponite® XLG-based silicate nanoplatelets, Laponite® XLS-based silicate nanoplatelets, Laponite® XL21-based silicate nanoplatelets, and Laponite® D-based silicate nanoplatelets).

[0023] The hydrogel compositions provided herein (eg, hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can contain any amount of nanosilicate. For example, the hydrogel compositions provided herein may contain from about 3% (w / v) to about 9% (w / v) nanosilicate (e.g., from about 4% (w / v) to about 9% (w / v) nanosilicate, from about 5% (w / v) to about 9% (w / v) nanosilicate, from about 6% (w / v) to about 9% (w / v) nanosilicate, from about 7% (w / v) to about 9% (w / v) nanosilicate, from about 8% (w / v) to about 9% (w / v) nanosilicate, from about 3% (w / v) to about 8% (w / v) nanosilicate, from about 3% (w / v) to about 7% (w / v) nanosilicate, from about 3% (w / v) to about 6% (w / v) nanosilicate, about 3% (w / v) to about 5% (w / v) nanosilicate, about 3% (w / v) to about 4% (w / v) nanosilicate, about 4% (w / v) to about 8% (w / v) nanosilicate, about 5% (w / v) to about 7% (w / v) nanosilicate, about 3% (w / v) to about 5% (w / v) nanosilicate, about 4% (w / v) to about 6% (w / v) nanosilicate, about 5% (w / v) to about 7% (w / v) nanosilicate, or about 6% (w / v) to about 8% (w / v) nanosilicate. In some cases, the hydrogel compositions provided herein may comprise about 9% (w / v) nanosilicate (e.g., silicate nanoplatelets). In some embodiments, the hydrogels of the present disclosure comprise about 2.5% to about 6% (w / w) nanosilicate (including about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, and about 6.0% and all values ​​and ranges therebetween). In some embodiments, the hydrogels comprise about 3.0% to about 4.0% (w / w) nanosilicate. In some embodiments, the hydrogels comprise about 3.25% to about 3.75% (w / w) nanosilicate. In some embodiments, the hydrogels comprise about 4.0% to about 5.5% (w / w) nanosilicate. In some embodiments, the hydrogel comprises about 4.25% to about 5.25% (w / w) nanosilicate.In some embodiments, the hydrogel comprises about 4.5% to about 5.0% (w / w) nanosilicate. In some embodiments, the hydrogel comprises about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, or about 5.5% (w / w) nanosilicate. In some embodiments, the hydrogel comprises about 4.75% (w / w) nanosilicate. In some embodiments, the hydrogel comprises about 4% (w / w) nanosilicate. In some embodiments, the hydrogel comprises about 3.5% (w / w) nanosilicate. The hydrogel compositions provided herein can have any ratio of gelatin to nanosilicate. For example, the hydrogel compositions provided herein can have a ratio of gelatin to nanosilicate of about 1:2 to about 1:9 (e.g., about 1:2 to about 1:8, about 1:2 to about 1:7, about 1:2 to about 1:6, about 1:2 to about 1:5, about 1:2 to about 1:4, about 1:3 to about 1:9, about 1:4 to about 1:9, about 1:5 to about 1:9, about 1:6 to about 1:9, about 1:7 to about 1:9, about 1:3 to about 1:8, about 1:4 to about 1:7, about 1:5 to about 1:6, about 1:2 to about 1:4, about 1:3 to about 1:6, about 1:4 to about 1:7, or about 1:5 to about 1:8). In some cases, the hydrogel compositions provided herein can have a ratio of gelatin to nanosilicate of about 1:6.

[0024] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may include water (e.g., ultrapure water). In some cases, the hydrogel compositions provided herein may have a ratio of gelatin to nanosilicates to water of about 1:5:6. In some cases, the hydrogel compositions provided herein may have a ratio of gelatin to nanosilicates to water of about 1:6:5.

[0025] The hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may include any type of radiopaque contrast agent. In some cases, the hydrogel compositions may include a single type of radiopaque contrast agent. In some cases, the hydrogel compositions may include more than one type (e.g., two, three, four, or more) of radiopaque contrast agents. Examples of radiopaque contrast agents that may be included in the hydrogel compositions provided herein include, but are not limited to, iodized molecules (e.g., iohexol, iopromide, iodixanol, ioaglate, iothalamate, and iopamidol), tantalum particles (e.g., tantalum nanoparticles), gold nanoparticles (AuNPs), ethyl iodized oil (e.g., Lipiodol®), lanthanide-based contrast agents, and bismuth. When the hydrogel compositions provided herein include tantalum particles, the tantalum particles can be any suitable size of tantalum particles. In some cases, the tantalum particles included in the hydrogel compositions provided herein can be essentially the same size. In some cases, the tantalum particles included in the hydrogel compositions provided herein can have different sizes. Examples of tantalum particles that can be included in the hydrogel compositions provided herein include, but are not limited to, tantalum microparticles (e.g., tantalum particles having an average size of about 2 μm) and tantalum nanoparticles (e.g., tantalum particles having an average size of less than about 25 nm). In some cases, the hydrogel compositions provided herein can include tantalum particles having an average size of about 2 μm. In some cases, the hydrogel compositions provided herein can include tantalum particles having an average size of about 30 μm. In some cases, the hydrogel compositions provided herein can include tantalum particles having an average size of about 2 nm.In some embodiments, the hydrogels of the present disclosure comprise tantalum particles having a median particle size of about 1 μm to about 15 μm (including about 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, and 14 μm and all values ​​and ranges therebetween). In some embodiments, the hydrogels of the present disclosure comprise tantalum particles having a median particle size of about 2 μm to about 5 μm.

[0026] Hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can include any amount of radiopaque contrast agent. For example, the hydrogel compositions provided herein can include from about 2% (w / w) to about 30% (w / w) (e.g., from about 2% (w / w) to about 25% (w / w), from about 2% (w / w) to about 20% (w / w), from about 2% (w / w) to about 15% (w / w), from about 2% (w / w) to about 10% (w / w), from about 2% (w / w) to about 5% (w / w), from about 5% (w / w) to about 30% (w / w), from about 10% (w / w) to about 30% (w / w), about 15% (w / w) ) to about 30% (w / w), about 20% (w / w) to about 30% (w / w), about 25% (w / w) to about 30% (w / w), about 5% (w / w) to about 25% (w / w), about 10% (w / w) to about 20% (w / w), about 5% (w / w) to about 10% (w / w), about 10% (w / w) to about 15% (w / w), about 15% (w / w) to about 20% (w / w), or about 20% (w / w) to about 25% (w / w). In some cases, the hydrogel compositions provided herein may include about 10% (w / w) of a radiopaque contrast agent (e.g., about 10% (w / w) iohexol). In some cases, the hydrogel compositions provided herein may include about 10% (w / w) radiopaque contrast agent (e.g., about 20% (w / w) tantalum particles, such as tantalum microparticles).

[0027] In some embodiments, the hydrogels of the present disclosure comprise about 10% (w / w) to about 30% (w / w) tantalum particles, including about 15%, about 20%, and about 25%, and all values ​​and ranges therebetween. In some embodiments, the hydrogels of the present disclosure comprise about 15% (w / w) to about 25% (w / w) tantalum particles. In some embodiments, the hydrogels of the present disclosure comprise about 20% (w / w) tantalum particles.

[0028] The hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be visualized (e.g., within a mammal) using any suitable method. For example, the hydrogel compositions provided herein can be visualized using imaging techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and / or fluoroscopy.

[0029] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may comprise 18% (w / v) gelatin, 9% (w / v) silicate nanoplatelets, and 10% (w / w) iohexol.

[0030] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may comprise 18% (w / v) gelatin, 9% (w / v) silicate nanoplatelets, and 20% (w / w) tantalum microparticles. In some embodiments, the present disclosure provides hydrogels comprising gelatin, silicate nanoplatelets, and tantalum microparticles. In some embodiments, the present disclosure provides hydrogels consisting essentially of gelatin, silicate nanoplatelets, tantalum microparticles, and water (e.g., deionized water).

[0031] In some embodiments, the hydrogel of the present disclosure comprises: about 15% to about 25% tantalum particles (w / w); about 2.5% to about 6% silicate nanoplatelets (w / w); about 0.2% to about 1.5% gelatin (w / w), and Contains water.

[0032] In some embodiments, the hydrogel of the present disclosure comprises: about 17.5% to about 22.5% tantalum particles (w / w); about 3.5% to about 6% silicate nanoplatelets (w / w); about 0.6% to about 1.0% gelatin (w / w), and Contains water.

[0033] In some embodiments, the hydrogel of the present disclosure comprises: Approximately 20% tantalum particles (w / w), Approximately 4.75% silicate nanoplatelets (w / w), About 0.8% gelatin (w / w), and Contains water.

[0034] In some embodiments, the hydrogel of the present disclosure comprises: about 15% to about 25% tantalum particles (w / w); about 2.0% to about 5% silicate nanoplatelets (w / w); about 0.4% to about 0.8% gelatin (w / w), and Contains water.

[0035] In some embodiments, the hydrogel of the present disclosure comprises: Approximately 20% tantalum particles (w / w), Approximately 4% silicate nanoplatelets (w / w), About 0.7% gelatin (w / w), and Contains water.

[0036] In some embodiments, the hydrogel of the present disclosure comprises: about 17.5% to about 22.5% tantalum particles (w / w); about 2.5% to about 4.5% silicate nanoplatelets (w / w); about 0.5% to about 0.7% gelatin (w / w), and Contains water.

[0037] In some embodiments, the hydrogel of the present disclosure comprises: Approximately 20% tantalum particles (w / w), Approximately 3.5% silicate nanoplatelets (w / w), About 0.6% gelatin (w / w), and Contains water.

[0038] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may be biodegradable. For example, the volume of the hydrogel composition delivered to a blood vessel in a mammal (e.g., a human) may decrease over time. In some cases, the volume of the hydrogel composition delivered to a blood vessel in a mammal (e.g., a human) may decrease by at least about 25% (e.g., at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 75%) over time. In some cases, the volume of the hydrogel composition delivered to a blood vessel in a mammal (e.g., a human) may decrease about 28 days after delivery. In some cases, the volume of the hydrogel composition delivered to a blood vessel in a mammal (e.g., a human) may decrease by about 75% over about 28 days after delivery.

[0039] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be shear thinning hydrogel compositions. For example, the viscosity of the hydrogel compositions provided herein can be about 10 -1 It can be reduced under a shear rate of 1 / s.

[0040] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions including gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can have a displacement pressure that is higher than the average pressure of a blood vessel (e.g., a healthy blood vessel or a blood vessel embolized with a coil). For example, the hydrogel compositions provided herein (e.g., hydrogel compositions including gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can have a displacement pressure of about 15 KPa to about 45 KPa.

[0041] The hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be made using any suitable method. In some cases, gelatin and one or more nanosilicates can be mixed first, and then one or more radiopaque contrast agents can be added. For example, centrifugal mixing, manual mixing, high shear dispersion, vacuum mixing, vortexing, and / or syringe mixing can be used to mix (e.g., homogeneously mix) gelatin, one or more nanosilicates, and one or more radiopaque contrast agents to make the hydrogel compositions provided herein. In some cases, the hydrogel compositions can be made as described in Example 1.

[0042] Optionally, the hydrogel compositions of the present invention may include one or more bioactive agents (e.g., embolic agents, anti-inflammatory agents, agents that modulate coagulation, antibiotic agents, chemotherapeutic agents, etc.). The hydrogel compositions of the present invention may be formulated for use as carriers or scaffolds for bioactive agents such as drugs, cells, proteins, and bioactive molecules (e.g., antibodies and enzymes). As carriers, such compositions may incorporate agents and be delivered to desired sites within the body for the treatment of various pathological conditions. Exemplary embolic agents include, for example, stainless steel coils, absorbable gelatin pledgets and powders, polyvinyl alcohol foams, ethanol, adhesives, etc. Exemplary hemostatic agents include, for example, Celox, QuikClot, and Hemcon. Certain exemplary materials and methods that can be adapted for use in such embodiments of the invention can be found, for example, in Hydrogels: Design, Synthesis and Application in Drug Delivery and Regenerative Medicine 1st Edition, Singh, Laverty and Donnelly (eds.), and Hydrogels in Biology and Medicine (Polymer Science and Technology) UK ed. Edition, J. Michalek et al. Additionally, as a scaffold, the compositions of the invention can provide a flexible residence space for cells and other agents for use in tissue repair and regeneration of desired tissues (e.g., cartilage, bone, retina, brain, and nerve tissue repair, vascular regeneration, wound healing, etc.).

[0043] In some cases, the hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be sterilized. Any suitable method can be used to sterilize the hydrogel compositions provided herein. For example, irradiation (e.g., ionizing irradiation), gamma irradiation, electron beam irradiation, gas (e.g., ethylene oxide)-based irradiation, and / or X-ray irradiation can be used to sterilize the hydrogel compositions provided herein. In some cases, the hydrogel compositions can be sterilized as described in Example 1.

[0044] Also provided herein are methods for using one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents). In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be used for embolization of one or more blood vessels in a mammal (e.g., a human). For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal for embolization of the blood vessels. In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be used for embolization without fragmentation of the delivered hydrogel composition. In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be used for embolization without migration of the hydrogel composition. In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be used for embolization with a recanalization rate of less than about 35% (e.g., less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%).

[0045] In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) to reduce or eliminate blood flow in the vessels. For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) to reduce blood flow in the vessels by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0046] In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) to induce clotting in the blood vessels. For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) to induce clotting in the blood vessels in less than about 20 minutes (e.g., less than about 15 minutes, less than about 12 minutes, less than about 10 minutes, less than about 8 minutes, or less than about 3 minutes). For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) to induce clotting in the blood vessels in less than about 0.5 cubic centimeters (cm 3 ) ~ approx. 5cm 3 (For example, about 0.5 cm 3 ~about 4.5cm 3 , about 0.5cm 3 ~about 4cm 3 , about 0.5cm 3 ~about 3.5cm 3 , about 0.5cm 3 ~about 3cm 3 , about 0.5cm 3~about 2.5cm 3 , about 0.5cm 3 ~ approx. 2cm 3 , about 0.5cm 3 ~approx. 1.5cm 3 , about 0.5cm 3 ~about 1cm 3 , about 1cm 3 ~about 5cm 3 , about 1.5cm 3 ~about 5cm 3 , about 2 cm 3 ~about 5cm 3 , about 2.5cm 3 ~about 5cm 3 , about 3cm 3 ~about 5cm 3 , about 3.5cm 3 ~about 5cm 3 , about 4cm 3 ~about 5cm 3 , about 4.5cm 3 ~about 5cm 3 , about 1cm 3 ~about 4.5cm 3 , about 1.5cm 3 ~about 4cm 3 , about 2 cm 3 ~about 3.5cm 3 , about 2.5cm 3 ~about 3cm 3 , about 0.5cm 3 ~approx. 1.5cm 3 , about 1.5cm 3 ~about 2.5cm 3 , about 2.5cm 3 ~about 3.5cm 3 , or about 3.5 cm 3 ~about 4.5cm 3 The present invention can induce the formation of a thrombus having a mass or size (e.g., volume) of 100 μm or more.

[0047] In some cases, one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) having a bleeding disorder to treat the mammal. For example, a hydrogel composition provided herein can be delivered to one or more blood vessels feeding one or more tumors in a mammal to reduce or eliminate blood flow associated with the bleeding disorder. Examples of bleeding disorders that can be treated as described herein (e.g., by delivering a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents to one or more blood vessels in a mammal) include, but are not limited to, hemorrhage (e.g., non-traumatic hemorrhage and traumatic hemorrhage), saccular aneurysm, vascular malformation, endoleak, gastroesophageal varices (e.g., bleeding gastroesophageal varices), and arteriovenous fistula.

[0048] In some cases, one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) having one or more tumors to treat the mammal. For example, a hydrogel composition provided herein can be delivered to one or more blood vessels feeding one or more tumors in a mammal to reduce or eliminate blood flow to the tumor. In some cases, the tumor can be a malignant tumor. In some cases, the tumor can be a benign tumor. Examples of tumors that can be treated as described herein (e.g., by delivering a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents to one or more blood vessels in a mammal) include, but are not limited to, liver tumors, uterine fibroids, prostate tumors, kidney tumors, and brain tumors. For example, one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels feeding one or more tumors in a mammal (e.g., a human) to reduce the size (e.g., volume) of the tumor by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or more percent.

[0049] In some cases, when one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are delivered to one or more blood vessels in a mammal (e.g., a human), the mammal may experience minimal or no embolization-related complications. Examples of embolization-related complications include, but are not limited to, vasospasm, thrombus formation, dissection, rupture, necrosis, bleeding at the puncture site, and hematoma at the puncture site.

[0050] One or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may be delivered to one or more blood vessels in any type of mammal. In some cases, the mammal (e.g., human) may be anticoagulated (e.g., may take one or more anticoagulants). In some cases, the mammal (e.g., human) may be coagulopathic (e.g., may have a bleeding disorder in which the mammal's blood is impaired in its ability to clot). Examples of mammals in which one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) may be delivered to one or more blood vessels in the mammal include, but are not limited to, humans, non-human primates, such as monkeys, dogs, cats, horses, cows, pigs, sheep, mice, rats, and rabbits.

[0051] One or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to any type of blood vessel in a mammal (e.g., human). In some cases, the blood vessel can be a diseased blood vessel. In some cases, the blood vessel can be an injured blood vessel. Examples of types of blood vessels to which the hydrogel compositions provided herein can be delivered include, but are not limited to, arteries, veins, and capillaries. When one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are delivered to an artery, the artery can be any artery in a mammal (e.g., human), such as a renal artery, an iliac artery, a gastric artery, a prostatic artery, or a mesenteric artery. When one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are delivered to a vein, the vein can be any vein within a mammal (e.g., a human), such as the portal vein and pelvic vein.

[0052] In some cases, one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to the lymphatic system in a mammal (e.g., a human).

[0053] In some cases, one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to the site of an endoleak (e.g., an endoleak in a vascular graft after repair).

[0054] One or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to blood vessels of any size in a mammal (e.g., a human). In some cases, blood vessels may be about 50 micrometers to about 10,000 micrometers (1 cm) (e.g., about 50 micrometers to about 5,000 micrometers, about 50 micrometers to about 1,500 micrometers, about 50 micrometers to about 1,000 micrometers, about 50 micrometers to about 900 micrometers, about 50 micrometers to about 800 micrometers, about 50 micrometers to about 700 micrometers, about 50 micrometers to about 600 micrometers, about 50 micrometers to about 500 micrometers, about 50 micrometers to about 400 micrometers, about 50 micrometers to about 300 micrometers, about 50 micrometers to about 200 micrometers, about 50 micrometers to about 100 micrometers, ... Chromium to about 10,000 micrometers, about 200 micrometers to about 10,000 micrometers, about 300 micrometers to about 10,000 micrometers, about 400 micrometers to about 10,000 micrometers, about 500 micrometers to about 10,000 micrometers, about 600 micrometers to about 10,000 micrometers, about 700 micrometers to about 10,000 micrometers, about 800 micrometers to about 10,000 micrometers, about 900 micrometers to about 10,000 micrometers, about 1,000 micrometers to about 10,000 micrometers, about 5,000 micrometers to about 10,000 micrometers, about 100 micrometers to about 5,000 micrometers, about 200 micrometers to about 1,The diameter (e.g., lumen diameter) of the tubular cavity may be about 1,000 micrometers, about 300 micrometers to about 900 micrometers, about 400 micrometers to about 800 micrometers, about 500 micrometers to about 700 micrometers, about 100 micrometers to about 400 micrometers, about 200 micrometers to about 500 micrometers, about 300 micrometers to about 600 micrometers, about 400 micrometers to about 700 micrometers, about 500 micrometers to about 800 micrometers, about 600 micrometers to about 900 micrometers, or about 700 micrometers to about 1,000 micrometers.

[0055] When delivering one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) to one or more blood vessels in a mammal (e.g., a human), any suitable delivery method can be used. In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) by direct injection into a blood vessel (e.g., a blood vessel requiring embolization). In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) by catheter-guided delivery (e.g., via a catheter inserted into a blood vessel requiring embolization). When one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are delivered to one or more blood vessels in a mammal (e.g., human) by catheter-guided delivery, any type of catheter (e.g., Bernstein catheter, microcatheter, Cobra catheter, Fogarty balloon, and ProGreat catheter) can be used. When one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are delivered to one or more blood vessels in a mammal (e.g., human) by catheter-guided delivery, any size of catheter can be used. For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., human) using a catheter having a size of about 2.8 French to about 5 French.

[0056] One or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) at any delivery rate. For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) at a rate of about 1 mL / min to about 2 mL / min.

[0057] Any amount of one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human). For example, about 2 mL to about 5 mL (e.g., about 2 mL to about 4 mL, about 2 mL to about 3 mL, about 3 mL to about 5 mL, about 4 mL to about 5 mL, about 2 mL to about 3 mL, or about 3 mL to about 4 mL) of one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human).

[0058] In some cases, after one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are used for embolization of one or more blood vessels in a mammal (e.g., a human), the hydrogel composition can be retrieved from the blood vessel. For example, after one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are delivered to one or more blood vessels in a mammal for embolization of the blood vessel, the hydrogel composition can be retrieved to increase (e.g., restore) blood flow through the blood vessel. Any suitable method can be used to retrieve one or more hydrogel compositions provided herein from one or more blood vessels in a mammal (e.g., a human). For example, one or more hydrogel compositions provided herein can be retrieved from one or more blood vessels in a mammal (e.g., a human) using an aspiration catheter (e.g., aspiration through a delivery catheter) and surgical removal.

[0059] In some cases, one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) as the sole active agent used for embolization.

[0060] In some cases, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) in combination with one or more additional agents used in embolization. For example, one or more hydrogel compositions provided herein (e.g., hydrogel compositions comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) can be delivered to one or more blood vessels in a mammal (e.g., a human) in combination with a solid embolic agent (e.g., coils, particles, foams, plugs, microspheres, and / or beads), a liquid embolic agent (e.g., butyl cyanoacrylate (n-BCA), and Onyx®).

[0061] When one or more hydrogel compositions provided herein (e.g., a hydrogel composition comprising gelatin, one or more nanosilicates, and one or more radiopaque contrast agents) are used in combination with an additional agent used in embolization, the one or more additional agents can be administered simultaneously (e.g., in the same composition or in separate compositions) or independently. For example, one or more hydrogel compositions provided herein can be administered first, followed by one or more additional agents, or vice versa.

[0062] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Working Example Example 1: Catheter-guided injectable biomaterials for rapid arterial embolization Evaluation of GEM performance in a rat model of femoral artery occlusion A major concern with gel-like embolic agents is that they may fragment during delivery, which can lead to non-targeted distal embolization and unintended tissue ischemia. To evaluate the stability of GEMs in high-velocity and high-pressure vasculature, a rat model of femoral artery occlusion was created. In this model, arterial flow in the femoral artery (FA) is occluded with GEMs. However, flow to the distal hindlimb is preserved by collateral flow. Any disruption of the GEMs will migrate distally in the rat's hindlimb and manifest as a loss of perfusion to that digit or limb. After direct delivery of GEMs to the FA (Figure 1A,B), high-resolution laser speckle contrast imaging (LSCI) demonstrated the absence of arterial flow (Figure 1C,D), confirming arterial occlusion by GEMs. To demonstrate flow to the hindlimb via collaterals, a 2 French microcatheter was delivered to the distal aorta via the carotid puncture, and digital subtraction angiography (DSA) using an iohexol-based contrast agent was performed. This confirmed FA occlusion and patency of collateral vessels, allowing blood flow to bypass the occluded segment of the FA (Figure 1E). After FA embolization, rats were allowed to survive for 0, 3, 7, or 21 days and serial assessment of hindlimb perfusion was performed using LSCI (Figure 1F,G). LSCI data demonstrated that hindlimb perfusion to the digits was preserved, indicating that GEMs in the FA remained at the injection site without fragmentation to the distal arterial system. Motor assessment of rats using the Tarlov scale also demonstrated normal motor activity after FA embolization with GEMs, which is consistent with angiograms showing sustained collateral perfusion to the hindlimb.

[0063] To assess the durability and biodegradability of GEMs in FAs, quantitative micro-CT imaging and histology were performed at days 0, 3, 7, and 21. Axial images of FAs at 10 micrometer resolution demonstrated uniform casting of the FA lumen, including smaller tortuous side branches such as the lateral circumflex artery (Figure 1H). The ability of GEMs to penetrate smaller arterial branches is an important property as this can prevent retrograde bleeding in a bleeding scenario. Micro-CT images demonstrated the progression of biodegradation (Figure 1H) and persistent occlusion of the artery with replacement of biomaterial by fibrotic tissue, which was confirmed by histology (Figure 1I). Extensive 3D morphometric analysis of the micro-CT datasets over time (Figure 7A-D) supported structural changes associated with material remodeling inside the arterial lumen.

[0064] GEM embolization of FA caused an initial dilation of the arterial lumen and thinning of the arterial wall, and after 21 days, the arterial wall thickened as the GEM biodegraded and remodeled to reduce arterial wall tension and decrease arterial lumen area (Figure 7E-L). To evaluate the immune response to GEM embolization, myeloperoxidase (MPO) and CD68 immunostaining were performed (Figure 7G-H). The number of MPO-stained cells in the arterial lumen peaked at day 3 after embolization (Figure 7K), consistent with an acute inflammatory response to GEM when neutrophils infiltrated the arterial lumen from the periphery. In contrast, CD68-stained cells peaked at day 21 after embolization (Figure 7L), suggesting that monocytes / macrophages play a role in the fibrotic remodeling process of the embolized arterial lumen.

[0065] To evaluate the efficacy of GEM embolization during anticoagulation therapy, the rat model of FA occlusion was repeated in heparinized rats with activated clotting time (ACT) values ​​of up to 300 seconds (Figure 8). MicroCT images showed that heparinization did not alter the morphometry of GEMs in the FA (Figure 8D). Furthermore, LASCI images showed no difference in distal perfusion of the hindlimb between heparinized and untreated rats (Figure 8E), and histology confirmed the presence of persistent casting of the FA lumen (Figure 8F, G). In this cohort of rats, GEMs remained localized at the site of FA injection without migration, fragmentation, or recanalization, suggesting that GEMs do not depend on clot formation at the GEM-blood interface to prevent migration and non-target embolization.

[0066] To evaluate the systemic response to GEM embolization, quantitative evaluation of 27 cytokines and chemokines was performed using rat serum isolated on days 0, 3, 7, and 21. The results show that there was no significant increase in proinflammatory mediators such as TNF-α, IL-1β, IL-6, and MIP-1α in serum samples compared to baseline. In contrast, there was a significant increase in anti-inflammatory cytokines such as IL-1α, IL-10, and IL-4, which peaked on day 7 and returned to baseline by day 21. These suggested that intra-arterial GEM infusion did not cause a systemic proinflammatory cytokine response, further supporting its biocompatibility and safety profile (Table 1).

[0067] Table 1. Serum levels of cytokines and chemokines after femoral artery embolization in rats. Multiplex analysis of cytokines and chemokines measured in rat serum 3, 7, and 21 days after femoral artery embolization. Results show a significant increase in IL-1a, IL-10, and IL-4 levels, which peaked on day 7 and then declined by day 21, compared to baseline on day 0, using analysis of variance. There was no change in serum levels of inflammatory cytokines compared to baseline controls on day 0. Results are mean ± SEM. Units are pg / ml, n=6 per group ( *P < 0.05, ** P<0.01; n=6). [Table 1]

[0068] Enhanced GEM visibility to enable embolization in large animal models Prior to testing GEMs in a porcine model of embolization, we optimized visualization of GEMs during real-time X-ray fluoroscopy, as this is critical to achieve targeted and controlled delivery. Clinically, metal coils used today for embolization are visible during fluoroscopy but generate significant artifacts associated with CT imaging, MRI, and US. The inability to evaluate the outcome of postembolization interventions due to artifacts is a major setback in today's clinical practice. Here, we present a formulation for GEMs that allows GEM and topographical anatomical visualization without significant artifacts in all imaging modalities, including CT, MRI, US, and fluoroscopy.

[0069] In rat experiments, GEMs made with 10% iohexol were insufficient for visualization by fluoroscopic imaging, as shown in Figure 1E. To improve the visualization of GEMs, tantalum (Ta) microparticles were used because Ta microparticles are already in clinical use in various medical devices. To introduce sufficient radiopacity to allow visualization during fluoroscopy, Ta microparticles or Ta nanoparticles with an average size of 2 μm were mixed with GEMs to form Ta-GEMs (e.g., 2–30% w / w Ta-GEMs) using a SpeedMixer. In CT phantom studies (Figures 2A, B), GEMs mixed with 20% tantalum were able to obtain satisfactory visibility without any streak artifacts. Fluoroscopy experiments showed that nano-Ta could not be distributed uniformly throughout the GEMs, resulting in poor visibility. Therefore, in subsequent experiments, micrometer-sized Ta particles in GEMs were used (Figures 2C, D). To test the visibility of Ta-GEMs in vivo, a 21G needle was used to percutaneously access the hepatic vein of a porcine liver under ultrasound guidance. In real time, both US and fluoroscopic imaging were performed during Ta-GEM injection, which showed sufficient visibility (Figure 2E,F). US imaging showed that the GEMs were echogenic, allowing for direct visualization. Furthermore, shear wave US imaging showed that the stiffness of the embolic agent did not increase significantly with the addition of Ta when compared to other samples with Ta (Figure 2G). Next, standard T1 and T2-based MRI of the syringe-loaded 20% Ta-GEMs was performed. As expected, the T1 sequence produced dark images, and the T2-based sequence produced bright images. This was expected given the MR properties of Ta and the hydrogel nature of the GEMs (Figure 2H-K). Analysis of the GEMs, including micro-CT, CT, MRI, and scanning electron microscope imaging, consistently demonstrated homogeneous dispersion of Ta in the GEMs, indicating an efficient kinetic mixing technique. This is important to provide a uniform signal during imaging (Figure 2L,M).

[0070] Evaluation of Ta-GEM injectability and shear thinning properties The ability to manually inject Ta-GEM loaded into a syringe connected to a clinical catheter was an important practical requirement in the design of GEM. To determine whether Ta-GEM is suitable for transcatheter delivery, the injectability of GEM and Ta-GEM through 2.8 French and 5 French clinical catheters, respectively, was examined using compression tests (Figure 3A). In both systems, Ta-GEM demonstrated injectability comparable to GEM, suggesting that the addition of Ta particles did not affect injectability (Figure 3B-E). Next, the effect of interrupting delivery was investigated. Again, no significant effect on injectivity was observed (Figure 3F). The ability to perform intermittent delivery while assessing embolization in real time is an important property and is not possible today with current technology.

[0071] In addition to injectability, the effect of Ta microparticles on the mechanical properties of GEM was analyzed using rheological testing. The flow curves of GEM and Ta-GEM demonstrate similar shear thinning properties (Figure 3G). To evaluate the embolism strength of GEM and Ta-GEM, amplitude oscillation tests were performed to measure their storage modulus G' and loss modulus G''. Figure 3H demonstrates that both GEM and Ta-GEM are viscoelastic, with G' values ​​that are approximately 10 times higher than G''. Furthermore, no significant change in G' (measured at 0.1% strain) was observed for Ta-GEM compared to GEM (Figure 3I), suggesting that the effect of Ta on the mechanical properties of GEM is minimal. These results suggested that the embolism strength of GEM and Ta-GEM was comparable. This was further confirmed by in vitro embolization experiments (Figure 3J-L). The displacement pressures of GEM and Ta-GEM were similar (35.8±3.9KPa and 33.2±2.6KPa, respectively; p=0.5), but significantly higher than the coil alone (9.9±1.5KPa, p<0.0001). More importantly, when Ta-GEM was combined with the coil, the displacement pressure reached 234.5±21.4KPa, or nearly 15 times greater than the standard physiological systolic pressure in humans. The additional strength from GEM combined with the coil is likely due to increased friction between the Ta particles and the coil.

[0072] Effect of tantalum on GEM thrombogenicity The enhanced thrombogenicity of Ta-GEM is a favorable property in an embolic agent to achieve vascular occlusion. Blood clotting in aliquots of citrated human blood mixed with Ta-GEM was compared to standard coils used in patients. Both coils, GEM and Ta-GEM, showed procoagulant properties when compared to blood alone. However, when the mass of the clot was measured, Ta-GEM showed a significant increase in mass from 3 min onwards compared to GEM and blood alone (Figure 9A,B). These results suggest that Ta-GEM has enhanced clotting properties, which may further stabilize the embolic material at the blood-GEM interface.

[0073] GEM sterilization A benchtop X-ray irradiator (RS2000, RAD.SOURCE) was used to sterilize the Ta-GEM. After exposure of GEM to 11 cGy / min of ionizing radiation for a total dose of 12,000 rads, sufficient to eradicate bacteria and fungi, there was no detectable microbial growth in the irradiated samples, confirming their sterility (Figure 9C). Furthermore, GEM prepared in non-sterile conditions on a laboratory benchtop also showed no evidence of microbial growth, suggesting that the composition of GEM itself is antimicrobial.

[0074] Testing Ta-GEM in a Porcine Model of Embolization The embolic efficacy of GEM was tested in a porcine arterial system. The experiment was designed to evaluate the performance of GEM compared to coils in embolizing primary arteries in heavily anticoagulated conditions. It was also investigated whether coils that failed to achieve hemostasis could be subsequently rescued by GEM injection into the coil mass, and whether GEM could be retrieved from the artery after injection. Today, there are no embolic coils capable of achieving hemostasis in anticoagulated conditions, or designed to be removed after delivery.

[0075] Iliac artery embolization in a porcine model using GEM Using clinical tools and imaging equipment, a combination of wire and catheter was used to deliver the catheter tip to the distal abdominal aorta. Digital subtraction angiography (DSA) characteristically showed the aorta bifurcating into a pair of external and internal iliac arteries. After intravenous administration of 20–30,000 units of heparin to achieve an ACT of >300 seconds, the iliac artery was catheterized. Approximately 6–7 cm of the iliac artery was subsequently embolized with GEM via a 5 French Bernstein catheter or a 2.8 French microcatheter (Figure 4; real-time delivery of GEM in vivo is shown in Figure 10A–C). DSA from the aortic bifurcation after embolization demonstrated immediate and complete focal occlusion of the target artery (Figure 4D, white arrows). For comparison, detachable 0.018 in. (0.0457 cm) or 0.035 in. (0.0889 cm) thick coils of various lengths were used to embolize the contralateral iliac artery. Despite deploying approximately 50-80 cm of coils with ACA above 300, these coils did not achieve hemostasis during the experimental period, which is consistent with clinical experience (Figure 4D,E; black arrows). Furthermore, on average, embolization times with GEM were 40 times faster than coil embolization, P<0.00001 (Figure 4D), demonstrating the unique aspects of GEM: simplicity and practicality of GEM delivery.

[0076] We next tested whether coils that failed to consistently achieve occlusion and hemostasis (e.g., Figure 4D) could be salvaged by injection of GEM. In eight cases in which the coils failed to function in anticoagulated conditions, immediate hemostasis and occlusion was possible by injection of 2–3 mL of GEM into the proximal end of the coil mass (Figure 4F). MicroCT imaging of embolized segments taken after autopsy demonstrated uniform casting of the iliac arteries by GEM without CT imaging artifacts even in high-resolution imaging, allowing the outcome of the intervention to be evaluated (Figure 4G, arrowheads). However, adjacent arterial segments embolized with coils showed large streak artifacts that precluded evaluation of the embolized adjacent arteries (Figure 4G, white arrows). These streak artifacts are commonly seen in patients undergoing CT scans. These limit the evaluation of the treated area and, in cases of cerebral aneurysms, often lead to the performance of invasive angiograms to evaluate the embolic effect.

[0077] Non-target embolization is always a concern in embolization. As a safety mechanism, we evaluated whether GEMs could be retrieved in the event of unintended or accidental non-target embolization. In five cases, we embolized the iliac artery with GEMs and, up to 3 hours later, completely retrieved the GEMs using the Penumbra Aspiration Catheter System, an FDA-approved device for stroke thrombectomy and restores flow (Figures 4H–J; Figures 10E–H). These results indicate that GEMs could be retrieved. These results also suggest for the first time that it may be possible to retrieve GEMs with temporary embolization and restore normal flow, for example, in patients with vascular trauma.

[0078] Survival study in a porcine model of iliac artery embolization using GEM We investigated the long-term outcomes of using GEMs in embolization of porcine iliac arteries while receiving daily antiplatelet therapy for anticoagulation. After surviving up to 28 days post-embolization, animals underwent contrast-enhanced CT angiography (CTA) and were then sacrificed. All 16 animals demonstrated persistent embolization at each time point, with no evidence of non-target embolization on CTA imaging (Figure 5). The embolized iliac arteries were occluded with GEMs, with no flow suggestive of recanalization. Lower hindlimb perfusion from the aorta to the ankle via collateral branches was also preserved (Figures 11A-C). There were no focal bright spots within the pelvic or hindlimb muscle compartments suggestive of GEM fragmentation and dislodgement (Figure 11B). General review of the porcine CTA images by a board-certified radiologist found the findings to be unremarkable (Figures 11D-L). For example, there was no evidence of lymphadenopathy, and solid organs, including the lungs, spleen, kidneys, and liver, were normal. Subsequently, at the time of necropsy, specimens from these organs were also collected for histological evaluation. Review of these slides by a certified pathologist showed normal findings. At the time of necropsy, the pelvic arteries were also dissected and immediately imaged using a high-resolution micro-CT scanner. Image analysis comparing the micro-CT data with the corresponding histology sections revealed progressive biodegradation of the GEMs at 4 weeks (Figure 5). Segmentation and 3D reconstruction of the iliac arteries using micro-CT datasets ranging from 700 Gb to 1 TB showed a gradual decrease in the volume of the GEMs (Figure 5B, black areas within each artery are GEMs) and a decrease in the luminal diameter of the embolized arteries. After 4 weeks, micro-CT volumetric analysis revealed that approximately 75% of the GEMs had biodegraded (Figure 5D). At day 0, the corresponding histology images showed homogenous occlusion of the iliac arteries with no significant tissue reaction and no cellular infiltration (Figure 5A). Over time, however, a concentric fibroinflammatory response occurs in the arterial lumen that is rich in macrophages, myofibroblasts, and fibrin resembling granulation tissue. As the GEM is gradually replaced by connective tissue, the biomaterial becomes infiltrated with MPO-positive granulocytes and scattered multinucleated giant cells. The majority of granulocytes are within the lumen of the artery (Figures 5A and 12), and both the internal and external elastic lamina show evidence of disruption, with disruption of elastic fibers in the intima and media layers and prominent fibrosis of the media layer (Figures 5A, 12C-E).As luminal fibrosis progressed, luminal diameter decreased 4 weeks after the initial dilation by GEM embolization (Fig. 5, H&E and trichrome staining). Medial thickness of the artery did not change over 4 weeks, in contrast to the rat arterial wall.

[0079] Complete blood counts (CBC), basic metabolic panel (BMP), liver function tests (LFT), and cytokine array analysis were performed to evaluate the systemic toxicity and inflammatory response to GEM. Pre-embolization samples were compared to blood samples obtained immediately prior to moribund sacrifice. Pre- and post-embolization blood tests, including CBC, LFT, and BMP, were found to be unremarkable (P>0.05, Table 2). This is an important result because it indicates that GEM does not consume platelets, activate acute phase reactants, increase white blood cell counts for infection, or damage solid organs. Cytokine array analysis of blood before and after embolization showed no signs of inflammation, with most factors reduced in the post-embolization samples (Table 3). These blood tests, cytokine analysis, histology, and cross-sectional imaging of the pigs further demonstrate that GEM is biocompatible and safe without evidence of adverse systemic responses.

[0080] Table 2. Complete blood count and serum chemistry profile in pigs after arterial embolization with GEM. The table shows blood values ​​measured 0, 1, 2, or 4 weeks after internal iliac artery embolization. WBC, white blood cells; HTC, hematocrit; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RDW, red blood cell distribution width; HGB, hemoglobin; RBC, red blood cells; MPV, mean platelet volume; ALP, alkaline phosphatase; CRE, creatinine; ALT, alanine aminotransferase; BUN, blood urea nitrogen. All measurements remained within the normal range for Yorkshire pigs. Results are mean ± SEM, in picograms / mL, n=4 per group ( * P<0.05). [Table 2]

[0081] Table 3. Serum levels of cytokines and chemokines after arterial embolization in pigs. Multiplex analysis of cytokines and chemokines 0, 1, 2, or 4 weeks after internal iliac artery embolization. Results showed no significant increase in all measurements. Results are mean ± SEM, in picograms / mL, n=4 per group. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNγ, interferon gamma; IL, interleukin; TNF, tumor necrosis factor. [Table 3]

[0082] Survival study in a porcine model of renal artery embolization using GEM Iliac artery embolization demonstrated that the GEM was stable with permanent occlusion (e.g., arterial occlusion without any evidence of throughflow on angiographic imaging indicating the embolization was stable) over a 28-day period. However, recanalization of the embolized arterial segment could not be definitively ruled out, as contrast enhancement was noted on CT images distal to the embolized iliac artery. This could be due to extensive transpelvic collateral flow or recanalization bypassing the embolized segment. To evaluate the possibility of recanalization of the GEM over time, the main renal artery of 16 swine was embolized. The kidney is composed of end-organ arteries, and successful embolization of the main renal artery results in distal ischemia and atrophy of the kidney. However, any recanalization of the GEM restores blood flow and reduces or eliminates atrophy. Furthermore, because the renal artery is a terminal artery, the smallest vessel that can be embolized by GEM was also determined and confirmed by histological examination.

[0083] The main renal artery was catheterized using a 5 French Cobra catheter and confirmed by DSA imaging (Figure 6A). Subsequently, 2–3 mL of GEM was injected and the artery was immediately occluded by casting (Figure 6B). DSA imaging from the aorta using the Cobra catheter consistently demonstrated total occlusion of the renal artery. Immediately prior to necropsy, imaging was performed using a clinical CT scanner (Figure 6C–E). These revealed no blood flow in the embolized kidney and progressive atrophy over the 28-day study period. By the fourth week, the embolized kidney consistently showed an approximately four-fold reduction in renal volume without any flow in the embolized renal artery or any distal arterial segments (Figure 6F–K). These data suggest no evidence of recanalization. Next, the kidneys were evaluated for any evidence of fragmentation and non-target embolization. Because the kidney is an end-organ artery, the 5-8 micrometer capillaries trap any detached GEMs and are visualized by micro-CT, near-infrared spectral imaging, and histology (Figure 13). This extensive analysis revealed that the renal cortex contained no evidence of GEMs. In further analysis, to determine the smallest artery into which GEMs could flow, a 4 French Fogarty balloon was inflated within the main renal artery to fix its position, and GEMs were subsequently injected through this Fogarty catheter. Infusion was stopped when the Fogarty balloon showed proximal displacement (Figure 13). Subsequent high-resolution micro-CT imaging revealed that the smallest arterial GEMs could be detected at approximately 320 micrometers, measured (Figure 13D-F). Furthermore, evaluation of the chest by a board-certified radiologist using axial and reformatted coronal images showed no evidence of focal hyperdensity or atelectasis that would suggest migration of embolic material from the renal arterioles to the capillaries (Figure 11E-F). Axial, coronal and sagittal images of the brain and digits were also negative for non-target embolism and for any evidence of ischemic changes or microvascular infarction (Figure 11).

[0084] Gelatin-based gelfoam embolization in porcine renal arteries The embolic performance of GEM was compared to Gelfoam, which is used clinically today for hemorrhage management. Similar to the gelatin used in GEM, Gelfoam is also composed of porcine gelatin. Pre-cut Gelfoam (EmboCube, Meritt Medical) was mixed with 50% v / v saline and 50% iohexol to create a slurry. These were subsequently used to embolize the renal artery, resulting in immediate occlusion (Figure 6L-M). After 2 weeks of survival, animals were imaged using a clinical CT scanner. These images demonstrated contrast enhancement of the kidney resulting from recanalization and sustained blood flow within the renal artery (Figure 6N). This was confirmed by the absence of Gelfoam inside the renal artery at necropsy and histology examination. These data suggest that GEM outperforms coils and Gelfoam, the current clinical tools used for embolization today.

[0085] Experimental section GEM synthesis and sterilization Iohexol-free GEMs were prepared by mixing 18% (w / v) gelatin (type A, Sigma Aldrich, St. Louis, MO, USA), 9% (w / v) silicate nanoplatelets (Laponite XLG, BYK USA Inc., Rochester Hills, MI, USA) and ultrapure water in a weight ratio of 1:6:5 as described elsewhere (see, e.g., Avery et al., Sci. Transl. Med., 8:365ra156 (2016) and Gaharwar et al., ACS Nano., 8:9833 (2014)). To introduce radiopacity, GEMs were mixed with iohexol or tantalum particles. Iohexol solution (Omnipaque 350 mgI / mL, GE HealthCare, MA) was mixed into GEMs to achieve a final concentration of 10% w / w. Tantalum microparticles (Ta) with an average size of 2 μm (Alfa Aesar, Haverhill, MA, USA) or tantalum nanoparticles with a particle size of less than 25 nm (Sigma-Aldrich, St. Louis, MO) were mixed with GEM at various w / w levels to form GEM-Ta hydrogels (e.g., 20% w / w Ta-GEM). Uniform mixing of all GEM formulations was achieved by using a SpeedMixer (FlackTek Inc., Landrum, SC). To sterilize GEM, the syringes loaded with GEM were exposed to an ionizing radiation dose of 160 kV, 25 mA (equivalent to 11 cGy / min) for a total of 12,000 rads using an RS2000 irradiation system (RAD.SOURCE) based on established protocols for eradicating bacteria and fungi. To confirm sterility, a standard microbial growth assay was performed using LB agar plates or LB broth with or without 100 mg / mL ampicillin. 7 ~10 8LB broth tubes harboring CFU of chemically competent E. coli were used as positive controls. LB broth tubes with 0.1 mL of PBS only were used as negative controls. Quadruplicate tubes were prepared from GEM batches and each control and incubated on a shaking platform in a 37°C incubator for up to 7 days. Analysis was performed as described in Avery et al., Sci. Transl. Med., 8:365ra156 (2016).

[0086] Rheological Testing Flow curves and amplitude sweeps were performed as described elsewhere (see, e.g., Avery et al., Sci. Transl. Med., 8:365ra156 (2016)). Rheological characterization of GEMs was performed using an Anton Paar MCR 302 rheometer (Anton Paar USA Inc., Torrance, CA, USA). Sandblasted 25 mm diameter aluminum top and bottom plates with a 500 μm gap between them were used for all measurements. Flow curves and amplitude sweeps (10 rad / s) were obtained at 25°C and 37°C. For the 37°C tests, a solvent trap was used, and the edges of the solvent trap were filled with water to provide a humidified environment. Data were acquired in at least triplicate for each experiment.

[0087] Analysis of GEM injectability Injectability was tested using a mechanical tester equipped with a 100 N load cell (Instron, Norwood, MA) according to a previously established protocol. Briefly, GEM was loaded into a 1 mL or 3 mL Luer-lock syringe (Medallion, Merit Medical, South Jordan, UT) and injected through a 110 cm 2.8 French ProGreat catheter (Terumo Medical Corporation, Somerset, NJ, USA) or a 100 cm 5F Bernstein catheter (Cook Medical Inc, Bloomington, IN), respectively. The GEM-containing syringe was inserted inside a custom-designed 3D-printed holder and the plunger was positioned against the load cell plate. Compressive force was applied at a rate of either 2 mL / min or 1 mL / min for the 5F and 2.8F, respectively. Interrupted compressive force was also applied for 10 seconds, followed by a 5-second pause, to simulate injection during clinical practice. This cycle was repeated 8 times through the 5 French catheter. The generated break and injection forces over time were acquired and plotted using Bluehill version-3 software (Instron, Norwood, MA, US). The injectability test was repeated at least five times for each condition.

[0088] Evaluation of the effect of GEM on blood clotting time Clotting time and clot weight were quantified as described elsewhere (see, e.g., Avery et al., Sci. Transl. Med., 8:365ra156 (2016), and Gaharwar et al., ACS Nano., 8:9833 (2014)). Briefly, 0.5 gram aliquots of GEMs were weighed into 2 mL microtubes. GEMs were centrifuged at 1000 RPM to standardize the blood interaction surface. Unclotted citrated blood was reactivated by adding 10% (v / v) 0.1 M CaCl2. 100 μL of activated blood was added to each GEM sample and allowed to react for 3, 8, 10, 12, 15, or 20 minutes. At each time point, clotting was stopped by adding 200 μL of 0.109 M sodium citrate solution. Residual liquid was removed and clotted blood was isolated. The clotted blood was weighed in each tube to determine the mass.

[0089] Rat model of femoral artery occlusion All in vivo studies were approved by the Institutional Animal Care and Use Committee (IACUC) and performed in accordance with federal and institutional guidelines. The right femoral artery was dissected between the proximal deep and superficial posterior epigastric arteries, away from the femoral vein and femoral nerve. Two 4-0 silk ligatures were wrapped around the distal and proximal ends to manipulate and stabilize the arterial segment during injection. A microvascular clamp was placed distal to the profunda branch. After GEM injection using a 27-gauge needle, rats were randomly divided into four groups and allowed to survive for 0, 3, 7, or 21 days (n=6 per group). Rats at day 0 were sacrificed 1 hour after GEM embolization and served as the control group. Each rat was serially imaged using laser speckle contrast imaging (LSCI) to quantify hindlimb microperfusion, and motor function was assessed using a modified Tarlov scale. Anesthetized rats were imaged in prone position on a heating table to maintain core body temperature at 37°C. After 5 min of stabilization, the laser was positioned above the rat at a set distance of 20 cm and perfusion imaging began. Data were acquired at baseline, immediately after injection, and 1 day after surgery, and then weekly thereafter. Perfusion data was calculated as the ratio of perfusion in the GEM-injected hind paw to the contralateral uninjected hind paw and expressed as a percentage of baseline.

[0090] Femoral artery occlusion in anticoagulated rats Six rats were administered heparin prior to GEM infusion into the femoral artery as described above and continued anticoagulation for 3 days after GEM infusion. Activated clotting times (ACT) were recorded using an iSTAT analyzer (Abbot, Princeton, NJ) in 0.25 mL blood aliquots taken from the superficial retroperitoneal vein before and after heparin administration. Once baseline ACT values ​​were recorded, 1200 IU / kg heparin diluted in 250 μL saline was injected intravenously into the femoral vein branch. These rats were subsequently administered 150 IU / kg heparin subcutaneously twice daily for 3 days after GEM infusion. A parallel group of six rats received a similar volume of saline instead of heparin to serve as a control group.

[0091] Percutaneous endovascular embolization in pigs This study was approved by the Institutional Animal Care and Use Committee (IACUC). Yorkshire pigs (S&S Farms, Brentwoods, CA) weighing 48–55 kg were acclimated for at least 4 days. Anesthesia was induced using an intramuscular injection of 5 mg / kg tiletamine-zolazepam (Telazol, Zoetis), 2 mg / mL xylazine, and 0.02 mg / kg glycopyrrolate. The pigs were then placed in a supine position and intubated on an X-ray compatible operating table (Pannomed Aeron, DRE, KY). After intubation, anesthesia was maintained by inhalation of 1.5–3% isoflurane. Electrocardiogram, transcutaneous oxyhemoglobin saturation (SpO2), end-tidal CO2 concentration, inspired oxygen fraction, and core temperature were monitored throughout the procedure. The carotid artery was accessed percutaneously using ultrasound guidance (ACUSON S2000, Siemens) and fluoroscopy (OEC9800 plus C-Arm, GE Healthcare Systems, Chicago, IL). The access needle and wire were exchanged for a 5 French Bernstein catheter (Cook Medical). The tip of the catheter was advanced into the renal or iliac artery using contrast fluoroscopy (350 mgI / mL Omnipaque, GE HealthCare, MA) via a GT-Glidewire (Terumo Medical). Pigs were administered 10,000–30,000 IU of heparin intravenously, and ACT values ​​were recorded using an iSTAT analyzer (Abbot Laboratories Princeton, NJ). GEM or EmboCube (Merit Medical) was delivered into the primary arterial branch of the iliac or renal artery using the catheter under real-time fluoroscopy guidance. A syringe with embolic agent was directly connected to the catheter using a Luer lock. In a subset, metallic coils, such as those manufactured by Medtronic, Terumo, Cook Medical, and Boston Scientific, were placed into the iliac arteries. The time to deployment of the GEM or coils was recorded for each procedure. After embolization, angiograms were repeated multiple times to assess vessel patency. Pigs were sacrificed 1 hour after embolization (non-survival group) or 1, 2, or 4 weeks after embolization (survival group).Prior to sacrifice, blood samples were collected for analysis and whole-animal CTA imaging was performed. At necropsy, vascular tissues containing GEMs or coils were excised for μCT imaging and histopathological evaluation. Liver, spleen, heart, and normal kidney tissues were also obtained and examined by histology to assess potential toxicity.

[0092] CT, US, MRI, and fluoroscopy acquisition methods CT acquisition was performed on a dual-source scanner (Siemens Force, Siemens Healthineers, Erlangen, Germany). Spiral scans were performed at energy levels of 150 kVp and 80 kVp, respectively, in a 0.6 mm detector size configuration. MRI acquisition was performed on a 3.0 T scanner (Siemens Skyra, Erlangen, Germany). Data were acquired using a 20-channel head coil with a body transmit coil. MRI acquisition consisted of axial single-shot T2, axial dual-echo in-phase and out-of-phase, pre-T1 weighted imaging, and balanced steady-state free precession. Fluoroscopy acquisition was performed on a mobile C-arm (OEC 9800 Plus, GE Healthcare, Illinois, USA).

[0093] Micro-CT imaging and structural analysis The excised embolized vessels were fixed in 10% formalin and incubated in 70% ethanol for 24 h. Micro-CT imaging was performed using a SkyScan 1276 (Bruker, Kontich, Belgium) at 33 kV and 223 μA for rat vessels and 45 kV and 200 μA for porcine arteries with a pixel size of 10 μm. Data analysis was performed using NRecon, CTvox, Data Viewer and CTAn software (Bruker, Kontich, Belgium). To document the structural changes in the injected GEMs, quantitative morphometric analysis was performed to calculate the surface-to-volume ratio, surface convexity index, fractal dimension, and structural model index. To calculate the GEM volume inside the embolized porcine vessels, the GEMs and vessel lumen were segmented using Mimics software (Materialise, Leuven, Belgium).

[0094] Histopathological and immunohistochemical examinations Paraffin-embedded sections were stained with H&E, Masson's Trichrome or EVG elastin stain, and immunostaining for myeloperoxidase (MPO; ab208670, Abcam) or CD68 (ab125212, Abcam) was performed as described elsewhere (see, e.g., Avery et al., Sci. Transl. Med., 8:365ra156 (2016)). Morphometric analysis was performed using image analysis software (Celleste 4.1, Thermo Fisher Scientific). MPO- or CD68-positive cells were counted by a blinded observer.

[0095] Multiplex analysis of serum Selected biomarkers, including cytokines, chemokines, and growth factors, were measured in serum samples obtained from aliquots of blood samples from rats at 0, 3, 7, and 21 days and from pigs at 0, 1, 2, and 4 weeks after embolization. Rat serum samples were analyzed using a cytokine / chemokine array 27-plex, and pig samples were analyzed using a porcine cytokine / chemokine array 13-plex (Eve Technologies, Calgary, CA). Analyte concentrations are expressed in picograms / mL.

[0096] statistical analysis Analysis between groups at different time points was performed using analysis of variance (ANOVA) with post-hoc multiple comparison procedure. Comparison between two groups was calculated using Student's t-test. Statistical significance of differences between groups was evaluated at the 95% confidence level (p<0.05). Data are presented as mean ± standard error of the mean (SEM). All comparisons we obtained were performed using GraphPad Prism 7 (GraphPad Software, Inc., La Jolla, CA).

[0097] Other embodiments Although the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0098] All publications mentioned herein (e.g., U.S. Patent Application Publication No. 2018 / 104059) are incorporated by reference herein to disclose and describe the aspects, methods and / or materials in connection with the cited publications.

[0099] Numbered Embodiments of the Disclosure 1. (a) gelatin; (b) nanosilicate; (c) tantalum.

[0100] 2. The hydrogel composition of embodiment 1, further comprising deionized water. 3. The hydrogel composition of embodiment 1 or 2, comprising about 15% to about 25% (w / w) tantalum.

[0101] 4. The hydrogel composition of any one of embodiments 1-3, comprising about 17.5% to about 22.5% (w / w) tantalum. 5. The hydrogel composition of any one of embodiments 1-3, comprising about 15%, about 17.5%, about 20%, about 22.5%, or about 25% (w / w) tantalum.

[0102] 6. The hydrogel composition of any one of embodiments 1-5, comprising about 20% (w / w) tantalum. 7. The hydrogel composition of any one of the preceding embodiments, wherein the nanosilicate is a silicate nanoplatelet.

[0103] 8. The hydrogel composition of any one of embodiments 1 to 7, comprising about 2.5% to about 6% (w / w) of nanosilicate. 9. The hydrogel composition of any one of embodiments 1 to 7, comprising about 3.0% to about 4.0% (w / w) of nanosilicate.

[0104] 10. The hydrogel composition of any one of the preceding embodiments, comprising about 3.25% to about 3.75% (w / w) of nanosilicate. 11. The hydrogel composition of any one of embodiments 1 to 7, comprising about 4.0% to about 5.5% (w / w) of nanosilicate.

[0105] 12. The hydrogel composition of any one of embodiments 1 to 7, comprising about 4.25% to about 5.25% (w / w) of nanosilicate. 13. The hydrogel composition of any one of embodiments 1 to 7, comprising about 4.5% to about 5.0% (w / w) of nanosilicate.

[0106] 14. The hydrogel composition of any one of embodiments 1-7, comprising about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, 4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%, or about 5.5% nanosilicate (w / w).

[0107] 15. The hydrogel composition of any one of embodiments 1-7, comprising about 4.75% (w / w) of nanosilicate. 16. The hydrogel composition of any one of embodiments 1 to 7, comprising about 4% (w / w) of nanosilicate.

[0108] 17. The hydrogel composition of any one of embodiments 1-7, comprising about 3.5% (w / w) of nanosilicate. 18. The hydrogel composition of any one of embodiments 7 to 17, wherein the median diameter of the silicate nanoplatelets is from about 1 μm to about 15 μm.

[0109] 19. The hydrogel composition of any one of embodiments 7 to 17, wherein the median diameter of the silicate nanoplatelets is from about 2 μm to about 5 μm. 20. The hydrogel composition of any one of embodiments 1-19, comprising about 0.2% to about 1.2% (w / w) gelatin.

[0110] 21. The hydrogel composition of any one of embodiments 1-19, comprising about 0.6% to about 1.0% (w / w) gelatin. 22. The hydrogel composition of any one of embodiments 1-19, comprising about 0.4% to about 0.8% (w / w) gelatin.

[0111] 23. The hydrogel composition of any one of embodiments 1-19, comprising about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, or about 1.2% (w / w) gelatin.

[0112] 24. The hydrogel composition of any one of embodiments 1-19, comprising about 0.6% (w / w) gelatin. 25. The hydrogel composition of any one of embodiments 1-19, comprising about 0.7% (w / w) gelatin.

[0113] 26. The hydrogel composition of any one of embodiments 1-19, comprising about 0.8% (w / w) gelatin. 27. The viscosity of the composition is about 10 -1 27. The hydrogel composition of any one of the preceding embodiments, wherein the hydrogel composition is reduced under a shear rate of 1 / s.

[0114] 28. The hydrogel composition of any one of the preceding embodiments, having a displacement pressure of about 15 KPa to about 45 KPa. 29. The hydrogel composition of any one of embodiments 1 to 28, which is sterile.

[0115] 30. A kit for use in embolization of a blood vessel comprising the hydrogel composition of any one of embodiments 1-29 packaged in a suitable container. 31. The kit according to embodiment 30, wherein the suitable container is a syringe.

[0116] 32. The kit of embodiment 30 or 31, wherein a suitable container contains from about 0.5 mL to about 5 mL of the hydrogel composition. 33. A kit according to any one of embodiments 29 to 32, wherein a suitable container contains about 0.5 mL, about 1.0 mL, about 1.5 mL, about 2.0 mL, about 2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, or about 5.0 mL of the hydrogel composition.

[0117] 34. A kit according to any one of embodiments 29 to 33, wherein a suitable container contains about 1.0 mL of the hydrogel composition. 35. A method for embolization of a blood vessel, in a patient in need thereof, comprising administering to the patient's blood vessel a therapeutically effective amount of a hydrogel composition according to any one of embodiments 1-29.

[0118] 36. The method of embodiment 35, wherein the maximum vessel diameter is about 3 mm. 37. The method of embodiment 35 or 36, wherein the composition is administered to the blood vessel by injection through a catheter.

[0119] 38. The method according to any one of embodiments 35 to 37, wherein the blood vessels are blood vessels of a hypervascularized tumor. 39. A method for embolizing bleeding and / or bleeding peripheral blood vessels in a patient in need thereof, comprising administering to the patient's blood vessel a therapeutically effective amount of a composition according to any one of embodiments 1-29.

[0120] 40. The method of embodiment 39, wherein the maximum vessel diameter is about 3 mm. 41. The method of embodiment 39 or 40, wherein the composition is administered to the blood vessel by injection through a catheter.

[0121] 42. The method of any one of embodiments 35-41, further comprising visualizing administration of the composition to the blood vessel by fluoroscopic visualization. 43. The method of any one of embodiments 35-41, further comprising determining administration of a therapeutically effective amount of the composition by fluoroscopic visualization.

[0122] 44. The method of any one of embodiments 35-43, wherein about 0.5 mL to about 5 mL of the composition is administered. 45. The method of any one of embodiments 35-44, wherein about 2 mL to about 5 mL of the composition is administered.

Claims

1. A hydrogel composition for embolization of one or more blood vessels, comprising: (a) gelatin; (b) a nanosilicate; and (c) a radiopaque contrast agent; the hydrogel composition comprises 2% (w / w) to 30% (w / w) of the radiopaque contrast agent; A hydrogel composition, wherein the radiopaque contrast agent is selected from iodized molecules selected from iohexol, iopromide, iodixanol, ioaglate, iothalamate, and iopamidol, and tantalum particles.

2. The hydrogel composition of claim 1, comprising 0.1% (w / v) to 20% (w / v) of the gelatin.

3. 3. The hydrogel composition of claim 2, comprising 18% (w / v) of said gelatin.

4. 4. The hydrogel composition of claim 2 or 3, wherein the gelatin is type A gelatin.

5. The hydrogel composition of claim 1, comprising 3% (w / v) to 9% (w / v) of the nanosilicate.

6. The hydrogel composition of claim 5, comprising 9% (w / v) of said nanosilicate.

7. 7. The hydrogel composition of claim 5 or 6, wherein the nanosilicate is a silicate nanoplatelet.

8. The hydrogel composition of claim 1, comprising 10% (w / w) of the radiopaque contrast agent, the radiopaque contrast agent comprising iohexol.

9. The hydrogel composition of claim 1, comprising 20% ​​(w / w) of the radiopaque contrast agent, the radiopaque contrast agent comprising tantalum particles.

10. The viscosity of the hydrogel composition is 10 －１ The hydrogel composition of any one of claims 1 to 9, which decreases under a shear rate of 1 / s.

11. The hydrogel composition of any one of claims 1 to 9, having a displacement pressure of 15 KPa to 45 KPa.

12. The hydrogel composition of claim 1, wherein the radiopaque contrast agent is tantalum particles.

13. The hydrogel composition of claim 1, wherein the radiopaque contrast agent is an iodized molecule selected from iohexol, iopromide, iodixanol, ioaglate, iothalamate, and iopamidol.

14. The hydrogel composition of claim 13, wherein the iodized molecule is iohexol.

15. The hydrogel composition of claim 1, comprising 5% (w / w) to 30% (w / w) of the radiopaque contrast agent.

16. The hydrogel composition of claim 1, comprising 10% (w / w) to 30% (w / w) of the radiopaque contrast agent.

17. The hydrogel composition of claim 1, comprising 15% (w / w) to 30% (w / w) of the radiopaque contrast agent.

18. The hydrogel composition of claim 1, wherein the hydrogel composition is used for embolization of a blood vessel in a mammal, and the hydrogel composition is delivered to the blood vessel.

19. The hydrogel composition of claim 1, wherein the hydrogel composition is used to reduce blood flow in a blood vessel in a mammal, and the hydrogel composition is delivered to the blood vessel.

20. The hydrogel composition of claim 1, wherein the hydrogel composition is used to induce clotting in a blood vessel in a mammal, and the hydrogel composition is delivered to the blood vessel.

21. 21. The hydrogel composition of claim 20, wherein the clotting is induced less than 20 minutes after the delivery.

22. The solidification is carried out in an area of ​​0.5 cubic centimeters (cm ３ ) ~5cm ３ 21. The hydrogel composition of claim 20, comprising the formation of a blot having a volume of 23. The hydrogel composition of claim 1, wherein the hydrogel composition is used to treat a mammal having a bleeding disorder, and the hydrogel composition is delivered to a blood vessel within the mammal.

24. 24. The hydrogel composition of claim 23, wherein the bleeding disorder is selected from the group consisting of non-traumatic hemorrhage, traumatic hemorrhage, saccular aneurysm, vascular malformation, endoleak, gastroesophageal varices, and arteriovenous fistula.

25. The hydrogel composition of claim 1, wherein the hydrogel composition is used to treat a mammal having a tumor, and the hydrogel composition is delivered to blood vessels in the mammal that nourish the tumor.

26. 26. The hydrogel composition of claim 25, wherein the tumor is a benign tumor.

27. 26. The hydrogel composition of claim 25, wherein the tumor is a malignant tumor.

28. 26. The hydrogel composition of claim 25, wherein the tumor is selected from the group consisting of a liver tumor, a uterine fibroid tumor, a prostate tumor, a kidney tumor, and a brain tumor.

29. The hydrogel composition of any one of claims 18 to 28, wherein the mammal is a human.

30. 30. The hydrogel composition of any one of claims 18 to 29, wherein the delivery comprises catheter-guided delivery.

31. 31. The hydrogel composition of any one of claims 18 to 30, wherein the delivery comprises a delivery rate of from 1 mL / min to 2 mL / min.

32. 32. The hydrogel composition of any one of claims 18-31, wherein the delivery comprises between 2 mL and 5 mL of the hydrogel composition.

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